Controlled release tramadol formulation

ABSTRACT

A controlled release preparation for oral administration contains tramadol, or a pharmaceutically acceptable salt thereof, as active ingredient.

[0001] The present invention relates to a controlled release preparationfor oral administration, to processes for its preparation and to itsmedical use. In particular, the invention relates to a controlledrelease preparation comprising tramadol or a pharmaceutically acceptablesalt thereof.

[0002] Tramadol, which has the chemical name(±)-trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol, isan orally active opioid analgesic. Conventional release preparations inthe form of capsules, drops and suppositories containing tramadol, ormore particularly its hydrochloride salt, have been commerciallyavailable for many years for use in the treatment of moderate to severepain; Such preparations, however, do not provide a controlled release ofthe tramadol. Moreover, despite tramadol's long-standing use, controlledrelease preparations for oral administration containing tramadol asactive ingredient have not even previously been described in theliterature.

[0003] It is an object of the present invention to provide an oralcontrolled release tramadol preparation suitable for at leasttwelve-hourly (e.g. up to twenty-four hourly) administration for thetreatment of pain.

[0004] The present invention therefore provides a controlled releasepreparation comprising tramadol or a pharmaceutically acceptable saltthereof for oral administration.

[0005] Suitable pharmaceutically acceptable salts of tramadol for useaccording to the present invention are those conventionally known in theart such as pharmaceutically acceptable acid addition salts. Thehydrochloride salt is particularly preferred.

[0006] A controlled release preparation according to the presentinvention is one that achieves slow release of a drug over an extendedperiod of time, thereby extending the duration of drug action over thatachieved by conventional delivery. Preferably such a preparationmaintains a drug concentration in the blood within the therapeutic rangefor 12 hours or more.

[0007] The present inventors have found that in order to allow forcontrolled release tramadol over at least a twelve hour-period followingoral administration, the in vitro release rate preferably corresponds tothe following % rate of tramadol released: TABLE 1 TIME (H) % RELEASED 10-50 2 0-75 4 3-95 8 10-100 12 20-100 16 30-100 24 50-100 36 >80

[0008] Another preferred preparation especially suited for twice-a-daydosing has an in vitro release rate corresponding to the following %rate of tramadol released: TABLE 2 TIME (H) % RELEASED 1 20-50 2 40-75 460-95 8  80-100 12  90-100

[0009] Yet another preferred preparation particularly suited foronce-a-day dosing has an in-vitro release rate corresponding to thefollowing % rate of tramadol released: TABLE 3 TIME (H) % RELEASED 10-50 2 0-75 4 10-95  8 35-100 12 55-100 16 70-100 24 >90

[0010] A still further preferred preparation in accordance with theinvention also particularly suited for once-a-day dosing has an in vitrorelease rate corresponding to the following % rate of tramadol released.TABLE 4 TIME (H) % RELEASED 1 0-30 2 0-40 4 3-55 8 10-65  12 20-75  1630-88  24 50-100 36 >80

[0011] More preferably a preparation for once-a-day dosing has an invitro release rate substantially as follows: TIME (H) % TRAMADOLRELEASED 1 15-25 2 25-35 4 30-45 8 40-60 12 55-70 16 60-75

[0012] Another preferred dissolution rate in vitro upon release of thecontrolled release preparation twice daily according to the invention,is between 5 and 50% (by weight) tramadol released after 1 hour, between10 and 75% (by weight) tramadol released after 2 hours, between 20 and95% (by weight) tramadol released after 4 hours, between 40 and 100% (byweight) tramadol released after 8 hours, more than 50% (by weight)tramadol released after 12 hours, more than 70% (by weight) releasedafter 18 hours and more than 80% (by weight) tramadol released after 24hours.

[0013] Furthermore, it is preferred in the case of a controlled releasepreparation for administration twice daily that after 8 hours followingoral administration between 70 and 95% (by weight) tramadol is absorbedin vivo, between 77 and 97% (by weight) tramadol is absorbed after 10hours and between 80 and 100% (by weight) tramadol is absorbed after 12hours.

[0014] A formulation in accordance with the invention suitable fortwice-a-day dosing may have a tmax of 1.5 to 8 hours, preferably 2 to 7hours, and a W₅₀ value in the range 7 to 16 hours.

[0015] A formulation in accordance with the invention suitable foronce-a-day dosing may have a tmax in the range of 3 to 6 hours,preferably 4 to 5 hours and a W₅₀ value in the range of 10 to 33 hours.

[0016] The W₅₀ parameter defines the width of the plasma profile at 50%Cmax, i.e. the duration over which the plasma concentrations are equalto or greater than 50% of the peak concentration. The parameter isdetermined by linear interpolation of the observed data and representsthe difference in time between the first (or only) upslope crossing andthe last (or only) downslope crossing in the plasma profile.

[0017] The in vitro release rates mentioned herein are, except whereotherwise specified, those obtained by measurement using the Ph. Eur.Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37° C. andusing UV detection at 270 nm.

[0018] The in viva absorption rate is determined from measurement ofplasma concentration against time using the deconvolution techniqiue. Aconventional release tramadol drop preparation (Tramal (trade mark),Grunenthal) was used as the weighting-function and the elimination halflife of tramadol was taken as 7.8 hours.

[0019] The controlled release preparation according to the inventionpreferably contains an analgesically effective amount of tramadol or apharmaceutically acceptable salt thereof, conveniently in the range offrom 50 to 800 mg, especially 100, 200, 300, 400 to 600 mg (calculatedas tramadol hydrochloride) per dosage unit.

[0020] The controlled release preparation according to the invention maybe presented, for example, as granules, spheroids, pellets,multiparticulates, capsules, tablets, sachets, controlled releasesuspensions, or in any other suitable dosage form incorporating suchgranules, spheroids, pellets or multiparticulates.

[0021] The active ingredient in the preparation according to theinvention may suitably be incorporated in a matrix. This may be anymatrix that affords controlled release tramadol over at least a twelvehour period and preferably that affords in-vitro dissolution rates andin vivo absorption rates of tramadol within the ranges specified above.Preferably the matrix is a controlled release matrix. Alternatively,normal release matrices having a coating which provides for controlledrelease of the active ingredient may be used.

[0022] Suitable materials for inclusion in a controlled release matrixinclude

[0023] (a) Hydrophillic or hydrophobic polymers, such as gums, celluloseethers, acrylic resins and protein derived materials. Of these polymers,the cellulose ethers, especially alkylcelluloses are preferred. Thepreparation may conveniently contain between 1% and 80% (by weight) ofone or more hydrophillic or hydrophobic polymers.

[0024] (b) Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀),substituted or unsubstituted hydrocarbons, such as fatty acids, fattyalcohols, glyceryl esters of fatty acids, mineral and vegetable oils andwaxes. Hydrocarbons having a melting point of between 25 and 90° C. arepreferred. Of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The preparation may conveniently contain up to60% (by weight) of at least one digestible, long chain hydrocarbon.

[0025] (c) Polyalkylene glycols. The preparation may suitably contain upto 60% (by weight) of one or more polyalkylene glycols.

[0026] One particularly suitable controlled release matrix comprises oneor more alkylcelluloses and one or more C₁₂-C₃₆ aliphatic alcohols. Thealkylcellulose is preferably C₁-C₆ alkyl cellulose, especially ethylcellulose. The controlled release preparation according to the inventionpreferably contains from 1 to 20% (by weight), especially from 2 to 15%(by weight) of one or more alkylcelluloses.

[0027] The aliphatic alcohol may conveniently be lauryl alcohol,myristyl alcohol or stearyl alcohol but is preferably cetyl alcohol ormore preferably cetostearyl alcohol. The controlled release preparationsuitably contains from 5 to 30% (by weight) of aliphatic alcohol,especially from 10 to 25% (by weight) of aliphatic alcohol.

[0028] Optionally the controlled release matrix may also contain otherpharmaceutically acceptable ingredients which are conventional in thepharmaceutical art such as diluents, lubricants, binders, granulatingaids, colourants, flavourants, surfactants, pH adjusters, anti-adherentsand glidants, e.g. dibutyl sebacate, ammonium hydroxide, oleic acid andcolloidal silica.

[0029] The controlled release preparation according to the invention mayconveniently be film coated using any film coating material conventionalin the pharmaceutical art. Preferably an aqueous film coating is used.

[0030] Alternatively, the controlled release preparation according tothe invention may comprise a normal release matrix having a controlledrelease coating. Preferably the preparation comprises film coatedspheroids containing the active ingredient and a spheronising agent.

[0031] The spheronising agent may be any suitable pharmaceuticallyacceptable material which may be spheronised together with the activeingredient to form spheroids. A preferred spheronising agent ismicrocrystalline cellulose. The microcrystalline cellulose used maysuitably be, for example, Avicel PII 101 or Avicel PII 102 (Trade Marks,FMC Corporation).

[0032] Optionally the spheroids may contain other pharmaceuticallyacceptable ingredients conventional in the pharmaceutical art such asbinders, bulking agents and colourants. Suitable binders include watersoluble polymers, water soluble hydroxyalkyl celluloses such ashydroxypropylcellulose or water insoluble polymers (which may alsocontribute controlled release properties) such as acrylic polymers orcopolymers for example ethylcellulose. Suitable bulking agents includelactose.

[0033] The spheroids are coated with a material which permits release ofthe active ingredient at a controlled rate in an aqueous medium.Suitable controlled release coating materials include water insolublewaxes and polymers such as polymethacrylates (for example Eudragitpolymers, Trade Mark) or water insoluble celluloses, particularlyethylcellulose. Optionally, water soluble polymers such aspolyvinylpyrrolidone or water soluble celluloses such ashydroxypropylmethylcellulose or hydroxypropylcellulose may be included.Optionally other water soluble agents such as polysorbate 80 may beadded.

[0034] Alternatively the drug may be coated onto inert non-pareil beadsand the drug loaded beads coated with a material which permits controlof the release of the active ingredient into the aqueous medium.

[0035] In a further aspect the present invention provides a process forpreparing a controlled release preparation according to the presentinvention comprising incorporating tramadol or a pharmaceuticallyacceptable salt thereof in a controlled release matrix, for example by

[0036] (a) granulating a mixture comprising tramadol or apharmaceutically acceptable salt thereof and one or morealkylcelluloses,

[0037] (b) mixing the alkylcellulose containing granules with one ormore C₁₂₋₃₆ aliphatic alcohols; and optionally

[0038] (c) shaping and compressing the granules, and film coating, ifdesired; or

[0039] (d) granulating a mixture comprising tramadol or apharmaceutically acceptable salt thereof, lactose and one or morealkylcelluloses with one or more C₁₂₋₃₆ aliphatic alcohol; and,optionally,

[0040] (e) shaping and compressing the granules, and film coating, ifdesired.

[0041] The controlled release preparation according to the invention mayalso be prepared in the form of film coated spheroids by

[0042] (a) granulating the mixture comprising tramadol or apharmaceutically acceptable salt thereof and a spheronising agent;

[0043] (b) extruding the granulated mixture to give an extrudate;

[0044] (c) spheronising the extrudate until spheroids are formed; and

[0045] (d) coating the spheroids with a film coat.

[0046] One preferred form of unit dose form in accordance with theinvention comprises a capsule filled with controlled release particlesessentially comprising the active ingredient, a hydrophobic fusiblecarrier or diluent and optionally a hydrophillic release modifier. Inparticular, the controlled release particles are preferably prepared bya process which comprises forming a mixture of dry active ingredient andfusible release control materials followed by mechanically working themixture in a high speed mixer with an energy input sufficient to melt orsoften the fusible material whereby it forms particles with the activeingredient, the resultant particles, after cooling, are suitably sievedto give particles having a size range from 0.1 to 3.0 mm, preferably0.25 to 2.0 mm. An example according to the invention is described belowwhich is suitable for the commercial production of dosage units.

[0047] When using such a processing technique it has been found that, inorder most readily to achieve the desired release characteristics (bothin vivo and in vitro as discussed above) the composition to be processedshould comprises two essential ingredients namely:

[0048] (a) tramadol or salt thereof; and

[0049] (b) hydrophobic fusible carrier or diluent; optionally togetherwith

[0050] (c) a release control component comprising a water-solublefusible material or a particulate soluble or insoluble organic orinorganic material.

[0051] We have found that the total amount of tramadol orpharmaceutically acceptable salt thereof in the composition may varywithin wide limits, for example from 10 to 90% by weight thereof.

[0052] The hydrophobic fusible component (b) should be a hydrophobicmaterial such as a natural or synthetic wax or oil, for examplehydrogenated vegetable oil, hydrogenated castor oil, microcrystallinewax, Beeswax, Carnauba wax or glyceryl monostearate, and suitably has amelting point of from 35 to 140° C., preferably 45 to 110° C.

[0053] The release modifying component (c), when a water soluble fusiblematerial, is conveniently a polyethylene glycol and, when a particulatematerial, is conveniently a pharmaceutically acceptable material such asdicalcium phosphate or lactose.

[0054] Another preferred process for the manufacture of a formulation inaccordance with the invention comprises

[0055] (a) mechanically working in a high-speed mixer, a mixture oftramadol or a pharmaceutically acceptable salt in particulate form and aparticulate, hydrophobic fusible carrier or diluent having a meltingpoint from 35 to 140° C. and optionally a release control componentcomprising a water soluble fusible material, or a particulate soluble orinsoluble organic or inorganic material at a speed and energy inputwhich allows the carrier or diluent to melt or soften, whereby it formsagglomerates,

[0056] (b) breaking down the larger agglomerates to give controlledrelease seeds; and

[0057] (c) continuing mechanically working with optionally a furtheraddition of low percentage of the carrier or diluent.

[0058] (d) optionally repeating steps (c) and possibly (b) one or moretimes.

[0059] This process is capable of giving a high yield (over 80%) ofparticles in a desired size range, with a desired uniformity of releaserate of tramadol or salt thereof.

[0060] The resulting particles may be sieved to eliminate any over-orundersized material then formed into the desired dosage units by forexample, encapsulation into hard gelatin capsules containing therequired dose of the active substance or by compression into tablets.

[0061] In this method in accordance with the invention preferaby all thetramadol or salt thereof is added in step (a) together with a majorportion of the hydrophobic fusible release control material used.Preferably the amount of fusible release control material added in step(a) is between 10% and 90% w/w of the total amount of ingredients addedin the entire manufacturing operation, more preferably between 20% and70% w/w.

[0062] Stage (a) of the process may be carried out in conventional highspeed mixers with a standard stainless steel interior, e.g. a ColletteVactron 75 or equivalent mixer. The mixture is processed until a bedtemperature about 40° C. or above is achieved and the resulting mixtureacquires a cohesive granular texture, with particle sizes ranging fromabout 1-3 mm to fine powder in the case of non-aggregated originalmaterial. Such material, in the case of the embodiments described below,has the appearance of agglomerates which upon cooling below 40° C. havestructural integrity and resistance to crushing between the fingers. Atthis stage the agglomerates are of an irregular size, shape andappearance.

[0063] The agglomerates are preferably allowed to cool. The temperatureto which it cools is not critical and a temperature in the range roomtemperature to 37° C. may be conveniently used.

[0064] The agglomerates are broken down by any suitable means, whichwill comminute oversize agglomerates and produce a mixture of powder andsmall particles preferably with a diameter under 2 mm. It is currentlypreferred to carry out the classification using a Jackson Crockattgranulator using a suitable sized mesh, or a Comil with an appropriatesized screen. We have found that if too small a mesh size is used in theaforementioned apparatus the agglomerates melting under the action ofthe beater or impeller will clog the mesh and prevent further throughputof mixture, thus reducing yield. A mesh size of 12 has been foundadequate.

[0065] The classified material is returned to the high speed mixer andprocessing continued. It is believed that this leads to cementation ofthe finer particles into particles of uniform size range.

[0066] In one preferred form of the method of the invention processingof the classified materials is continued, until the hydrophobic fusiblematerials used begin to soften/melt and optionally additionalhydrophobic fusible material is then added. Mixing is continued untilthe mixture has been transformed into particles of the desiredpredetermined size range.

[0067] In order to ensure uniform energy input into the ingredients inthe high speed mixer it is preferred to supply at least part of theenergy by means of microwave energy.

[0068] Energy may also be delivered through other means such as by aheating jacket or via the mixer impeller and chopper blades.

[0069] After the particles have been formed they are cooled or allowedto cool, and may then be sieved to remove any over or undersizedmaterial.

[0070] The resulting particles may be used to prepare dosage units inaccordance with the invention in the form of e.g. tablets or capsules inmanners known per se.

[0071] We have also found that particles containing tramadol or a saltthereof produced by a melt processing as described in applicationPCT/SE93/00225 and the process described and claimed in our priorunpublished UK application No. 9324045.5 filed on Nov. 23, 1993 as wellas the process described herein are particularly useful for processinginto the form of tablets.

[0072] We have found that by suitable selection of the materials used informing the particles and in the tabletting and the proportions in whichthey are used, enables a significant degree of control in the ultimatedissolution and release rates of the tramadol or salt thereof from thecompressed tablets.

[0073] Usually, to form a tablet in accordance with the invention,particles prepared as described above will be admixed with tablettingexcipients e.g. one or more of the standard excipients such as diluents,lubricants, binding agents, flow aids, disintegrating agents, surfaceactive agents or water soluble polymeric materials.

[0074] Suitable diluents are e.g. microcrystalline cellulose, lactoseand dicalcium phosphate. Suitable lubricants are e.g. magnesium stearateand sodium stearyl fumarate. Suitable binding agents are e.g.hydroxypropyl methyl cellulose, polyvidone and methyl cellulose.

[0075] Suitable disintegrating agents are starch, sodium starchglycolate, crospovidone and croscarmalose sodium. Suitable surfaceactive are Poloxamer 188®, polysorbate 80 and sodium lauryl sulfate.Suitable flow aids are talc colloidal anhydrous silica. Suitable watersoluble polymers are PEG with molecular weights in the range 1000 to6000.

[0076] To produce tablets in accordance with the invention, particlesproduced in accordance with the invention may be mixed or blended withthe desired excipient(s), if any, using conventional procedures, e.g.using a Y-Cone or bin-blender and the resulting mixture compressedaccording to conventional tabletting procedure using a suitable sizetabletting mould. Tablets can be produced using conventional tablettingmachines, and in the embodiments described below were produced onstandard single punch F3 Manesty machine or Kilian RLE15 rotary tabletmachine.

[0077] Generally speaking we find that even with such a highly watersoluble active agent as tramadol or salt thereof tablets formed bycompression according to standard methods give very low release rates ofthe active ingredient e.g. corresponding to release over a period ofgreater than 24 hours, say more than 36. We have found that the releaseprofile can be adjusted in a number of ways. For instance a higherloading of the drug will be associated with increased release rates; theuse of larger proportions of the water soluble fusible material in theparticles or surface active agent in the tabletting formulation willalso be associated with a higher release rate of the active ingredient.By controlling the relative amounts of these ingredients it is possibleto adjust the release profile of the tramadol or salt thereof.

[0078] In order that the invention may be well understood the followingexamples are given by way of illustration only.

EXAMPLE 1

[0079] Tablets having the following formulation were prepared: mg/tabletTramadol Hydrochloride 100 Lactose Ph. Eur. 68.0 Ethylcellulose(Surelease ® 25% solids) 15 Purified Water Ph. Eur. 13.3* CetostearylAlcohol Ph. Eur. 42.00 (Dehydag wax O) Magnesium Stearate Ph. Eur. 2.00Purified Talc Ph. Eur. 3.00 230.00

[0080] Tramadol hydrochloride (100 mg) and lactose (68 mg) weregranulated, transferred to a fluid bed granulator and sprayed withethylcellulose (15 mg) and water. The granules were then dried at 60° C.and passed through a 1 mm screen.

[0081] To the warmed tramadol containing granules was added moltencetostearyl alcohol (42 mg) and the whole was mixed thoroughly. Thegranules were allowed to cool and sieved through a 1.6 mm screen.Purified talc and magnesium stearate were added and mixed with thegranules. The granules were then compressed into tablets.

[0082] The tablets were coated with a film coat having the formulationgiven below. mg/tablet Hydropropylmethylcellulose 0.770 Ph. Eur. 15 cps(Methocel E15) Hydroxypropylmethylcellulose 3.87 (Ph. Eur. 5 cps(Methocel E5) Opaspray M-1-7111B (33% solids) 2.57 Polyethylene glycol400 USNF 0.520 Purified Talc Ph. Eur. 0.270 Purified Water Ph. Eur.55.52*

EXAMPLE 2

[0083] Tablets having the following formulation were prepared: mg/tabletTramadol hydrochloride 100.0 Lactose Ph. Eur. 58.0 Ethylcellulose USNF15.0 (Ethocel 45 CP) Cetostearyl alcohol Ph. Eur. 52.0 (Dehydag wax O)Magnesium stearate Ph. Eur. 2.00 Purified talc Ph. Eur. 3.00

[0084] A mixture of tramadol hydrochloride (100 mg), lactose (58 mg) andethylcellulose (15 mg) was granulated whilst adding molten cetostearylalcohol (52 mg) and the whole was mixed thoroughly. The granules wereallowed to cool and sieved through a 1.6 mm screen. Purified talc andmagnesium stearate were added and mixed with the granules. The granuleswere then compressed into tablets which were coated with a film coathaving the formulation given in Example 1.

EXAMPLE 3

[0085] Film coated tablets were produced following the proceduredescribed in Example 2 and having the following formulation: mg/tabletTramadol hydrochloride 100.00 Lactose Ph. Eur. 70.50Hydroxyethylcellulose Ph. Eur. 12.50 Cetostearyl alcohol Ph. Eur. 42.00Magnesium stearate Ph. Eur. 2.00 Purified talc Ph. Eur. 3.00

[0086] In Vitro Dissolution Studies

[0087] In vitro dissolution studies were conducted on tablets preparedas described above. Results are given in Table 1. TABLE 1 WT % TRAMADOLRELEASED Time (h) Example 1 Example 2* Example 3 1 39 35 43 2 52 47 60 467 62 84 8 82 78 97 12 90 86 —

[0088] In a trial involving 12 healthy volunteers the serum levels oftramadol following administration of one tablet according to Example 2was found to be as illustrated in FIG. 1.

EXAMPLE 4 AND 5

[0089] Particles having the formulations given in Table 11 below wereprepared by the steps of:

[0090] i. Placing the ingredients (a) and (c) (total batch weight 0.7kg) in the bowl of a liter capacity Collette Gral Mixer (or equivalent)equipped with variable speed mixing and granulating blades;

[0091] ii. Mixing the ingredients at about 150-1000 rpm whilst applyingheat until the contents of the bowl are agglomerated.

[0092] iii. Classifying the agglomerated material by passage through aComil and/or Jackson Crockatt to obtain controlled release seeds.

[0093] iv. Warming and mixing the classified material in the bowl of a10 liter Collette Gral, until uniform multiparticulates of the desiredpre-determined size range are formed in yield of greater than 80%. Thistakes approximately 5 minutes.

[0094] v. Discharging the multiparticulates from the mixer and sievingthem to separate out the multiparticulates collected between 0.5 and 2mm aperture sieves. TABLE II Example 4 5 (a) Tramadol HCl (Wt %) 50 75(b) Hydrogenated Vegetable Oil (Wt %) 50 25

EXAMPLE 6

[0095] Samples of the particles from Example 4 were blended withmagnesium stearate and purified talc using a Y-Cone or bin-blender. Theblended mixture was then compressed using either (1) 14×6 mm, (2) 16×7mm or (3) 18.6×7.5 mm capsule shaped tooling on a single punch F3Manesty tabletting machine to give tablets giving 200, 300 and 400 mg oftramadol HCl. The ingredients per dosage unit amounted to the following:TABLE III TABLET MG/TABLET INGREDIENT 1 2 3 Tramadol HCl 200 300 400Hydrogenated Vegetable Oil 200 300 400 Sub Total 400 600 800 PurifiedTalc 12.63 18.95 25.26 Magnesium Searate 8.42 12.63 16.84

[0096] The tablets were assessed by the dissolution using Ph. Eur.Paddle Method 100 rpm, 0.1 N HCl.

[0097] To assess the non-compressed particles the Ph Eur. Paddle wasreplaced by a modified Ph Eur. Basket.

[0098] The results are shown in Table IV below; TABLE IV HOURS AFTERParticles Tablet 1 Tablet 2 Tablet 3 START OF TEST % TRAMADOL HClRELEASED 1 54 16 15 15 2 68 23 20 21 3 76 28 25 25 4 82 32 28 28 6 89 4035 35 8 93 46 41 40 10 96 50 45 45 12 98 55 49 49 16 100  63 57 56 20 NR70 63 NR

[0099] These results confirm the effectiveness of the tabletting inreducing the release rate.

EXAMPLE 7

[0100] Samples of the particles from Example 5 were then tabletted usinga procedure similar to Example 3 and the ingredients per unit dosageamounted to: TABLE V TABLET MG/TABLET INGREDIENT 4 5 6 Tramadol HCl 200300 400 Hydrogeziated Vegetable Oil 66.7 100 133 Sub Total 266.7 400 533Purified Talc 7.63 11.44 15.25 Magnesium Stearate 5.16 7.63 10.17

[0101] The tablets and samples of non-compressed multiparticulates (eachsample containing 400 mg of tramadol hydrochloride) were assessed by thedissolution method also described above. The results are shown in TableVI below; TABLE VI HOURS AFTER Particles Tablet 4 Tablet 5 Tablet 6START OF TEST % TRAMADOL HCl RELEASED 1  77 43 40 42 2  92 64 55 56 3 98 75 65 66 4 100 83 72 73 6 102 94 83 84 8 102 100  91 91 10 102 NR 9697

[0102] These results show that by increasing the loading of the highlywater soluble tramadol hydrochloride (75% w/w in this example comparedwith 50% w/w in Example 6) a significantly faster release rate of theactive ingredient can be achieved.

EXAMPLE 8

[0103] Example 4 was repeated but with the following formulation:Tramadol HCl 200 mg/tablet Hydrogenated Vegetable Oil 163.0 mg/tablet

[0104] The resulting multiparticulates were blended as described inExample 6 with the following; Purified Talc 11.5 mg/tablet MagnesiumStearate 7.66 mg/tablet

[0105] The blend was then compressed as described in Example 6 but using15 mm×6.5 mm normal concave capsule shaped plain/plain punches.

[0106] The resulting tablets were then assessed by the dissolutionmethod described above. The results are shown in Table V. HOURS AFTERSTART OF TEST % TRAMADOL HCl RELEASED 1 20 2 27 3 32 4 37 6 44 8 50 1055 12 60 16 67 20 73 24 77

[0107] In a trial involving five healthy male volunteers the plasmaprofile resulting from single dose administrations of the above tabletare shown in FIG. 2 in comparison to the administration of a commercialpreparation of Tramadol drops 100 mg.

What is claimed is:
 1. A controlled release preparation comprisingtramadol or a pharmaceutically acceptable salt thereof for oraladministration.
 2. A controlled release preparation as claimed in claim1 containing from about 50 to about 800 mg of tramadol (calculated astramadol hydrochloride).
 3. A controlled release preparation as claimedin claim 1 , having an in-vitro dissolution rate (measured by the Ph.Eur. Paddle method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C. and using UV detection at 270 mm) as set forth below: TIME (H) %RELEASED 1 0-50 2 0-75 4 3-95 8 10-100 12 20-100 16 30-100 24 50-100 36>80


4. A controlled release preparation as claimed in claim 1 , having anin-vitro dissolution rate (measured by the Ph. Eur. Paddle method at 100rpm in 900 ml 0.1 N hydrochloric acid at 37° C. and using UV detectionat 270 mm) as set forth below: TIME (H) % RELEASED 1 20-50 2 40-75 460-95 8  80-100 12   90-100


5. A controlled release preparation as claimed in claim 1 , having anin-vitro dissolution rate (measured by the Ph. Eur. Paddle method at 100rpm in 900 ml 0.1 N hydrochloric acid at 37° C. and using UV detectionat 270 mm) as set forth below: TIME (H) % RELEASED 1 0-50 2 0-75 410-95  8 35-100 12 55-100 16 70-100 24 >90


6. A controlled release preparation as claimed in claim 1 , having anin-vitro dissolution rate (measured by the Ph. Eur. Paddle Method at 100rpm in 900 ml 0.1 N hydrochloric acid at 37° C. and using UV detectionat 270 mm) as set forth below: TIME (H) % RELEASED 1 0-30 2 0-40 4 3-558 10-65  12 20-75  16 30-88  24 50-100 36 >80


7. A controlled release oral dosage form according to claim 1 ,comprising a therapeutically effective amount of tramadol or a saltthereof in a matrix adapted to provide a controlled release of thetramadol or salt thereof upon oral administration.
 8. A dosage formaccording to claim 7 , wherein said matrix comprises a controlledrelease matrix comprising at least one alkylcellulose, at least one C₁₂to C₃₆, aliphatic alcohol and, optionally at least one polyalkylglycol.9. A dosage form as claimed in claim 8 , wherein said optionally atleast one polyalkylglycol is polyethylene glycol.
 10. A dosage formaccording to claim 8 , wherein said at least one C₁₂ to C₃₆ aliphaticalcohol is a C₁₄ to C₂₂ aliphatic alcohol.
 11. A dosage form accordingto claim 8 , wherein said alkylcellulose is a C₁-C₆ alkylcellulose. 12.A dosage form according to claim 8 , characterized in that the dosageform contains from about 1 to about 20% w/w, preferably from about 2 toabout 15% w/w of one or more alkylcelluloses.
 13. A dosage formaccording to claim 8 , wherein said aliphatic alcohol is selected fromthe group consisting of lauryl alcohol, myristyl alcohol,stearylalcohol, cetyl alcohol, cetostearyl alcohol, and mixtures of anyof the foregoing.
 14. The dosage form of claim 13 , wherein saidaliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
 15. A dosageform according to claim 8 , wherein said dosage form contains from about5 to bout 30% w/w of aliphatic alcohol.
 16. A dosage form according toclaim 8 , wherein aid dosage form contains from about 10 to about 25%w/w of aliphatic alcohol.
 17. A dosage form according to claim 1 , inthe form of film coated spheroids, wherein said spheroid matrixcomprises a spheronizing agent, preferably microcrystalline cellulose.18. A dosage form according to claim 1 , in the form ofmultiparticulates wherein said matrix comprises a hydrophobic fusiblecarrier or diluent having a melting point from 35 to 140° C. andoptionally a release control component comprising a water solublefusible material, or a particulate soluble or insoluble organic orinorganic material.
 19. A dosage form according to claim 1 , whichcomprises a tablet formed by compressing a multiparticulate according toclaim 18 .
 20. A process for the preparation of a solid, controlledrelease oral dosage form, comprising incorporating a therapeuticallyeffective amount of tramadol or a pharmaceutically acceptable saltthereof in a matrix adapted to provide a controlled release of thetramadol or salt thereof upon oral administration.
 21. A processaccording to claim 20 , wherein from about 50 to about 800 mg oftramadol (calculated as tramadol hydrochloride) is incorporated in thedosage form.
 22. A process according to claim 20 , wherein thedissolution rate (measured by the Ph. Eur. Paddle method at 100 rpm in900 ml 0.1 N hydrochloric acid at 37° C. and using UV detection at 270mm) is as set forth below: TIME (H) % RELEASED 1 0-50 2 0-75 4 3-95 810-100 12 20-100 16 30-100 24 50-100 36 >80


23. A process according to claim 20 , wherein the dissolution rate(measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 Nhydrochloric acid at 37° C. and using UV detection at 270 mm) is as setforth below: TIME (H) % RELEASED 1 0-50 2 0-75 4 10-95  8 35-100 1255-100 16 70-100 24 >90


24. A process according to claim 20 , wherein the dissolution rate(measured by the Ph. Eur. Paddle method at 100 rpm in 900 ml 0.1 Nhydrochloric acid at 37° C. and using UV detection at 270 mm) is as setforth below: TIME (H) % RELEASED 1 0-50 2 0-40 4 3-55 8 10-65  12 20-75 16 30-88  24 50-100 36 >80


25. A process according to claim 20 , wherein said matrix comprises acontrolled release matrix comprising at least one C₁ to C₆alkylcellulose, at least one C₁₂ to C₃₆, aliphatic alcohol and,optionally at least one polyalkylglycol.
 26. A process according toclaim 25 , wherein said aliphatic alcohol is a C₁₄ to C₂₂ aliphaticalcohol.
 27. A process according to claim 25 wherein said optionally atleast one polyalkylglycol is polyethylene glycol.
 28. A processaccording to claim 20 , wherein said at least one alkylcellulose isethylcellulose.
 29. A process according to claim 20 , wherein saiddosage form comprises from about 1 to about 20% w/w of one or morealkylcelluloses.
 30. A process according to claim 29 , wherein saiddosage form contains from about 2 to about 15% w/w of one or morealkylcelluloses.
 31. A process according to claim 20 , wherein saidaliphatic alcohol comprises lauryl alcohol, myristyl alcohol orstearylalcohol.
 32. A process according to claim 31 , wherein saidaliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
 33. A processaccording to claim 20 , wherein said dosage form comprises from about 5to about 30% w/w of aliphatic alcohol.
 34. A process according to claim33 , wherein said dosage form comprises from about 10 to about 25% w/wof aliphatic alcohol.
 35. A process according to claim 20 , furthercomprising: (a) granulating a mixture comprising tramadol or apharmaceutically acceptable salt thereof and one or morealkylcelluloses, (b) mixing the alkylcellulose containing granules withone or more C₁₂-₃₆ aliphatic alcohols; and, optionally (c) shaping andcompressing the granules, and film coating, if desired.
 36. A processaccording to claim 20 , further comprising: (a) granulating a mixturecomprising tramadol or a pharmaceutically acceptable salt thereof,lactose and one or more alkylcelluloses with one or more C₁₂₋₃₆aliphatic alcohol; and, optionally, (b) shaping and compressing thegranules, and film coating.
 37. A process according to claim 20 ,further comprising: (a) granulating the mixture comprising tramadol or apharmaceutically acceptable salt thereof and a spheronizing agent; (b)extruding the granulated mixture to give an extrudate; (c) spheronizingthe extrudate until spheroids are formed; and (d) coating the spheroidswith a film coat.
 38. A process according to claim 20 , comprising: (a)mechanically working in a high-speed mixer, a mixture of tramadol or apharmaceutically acceptable salt thereof in particulate form and aparticulate, hydrophobic fusible carrier or diluent having a meltingpoint from 35 to 140° C. and optionally a release control componentcomprising a water soluble fusible material, or a particulate soluble orinsoluble organic or inorganic material at a speed and energy inputwhich allows the carrier or diluent to melt or soften, whereby it formsagglomerates; (b) breaking down the larger agglomerates to givecontrolled release seeds; (c) continuing mechanically working withoptionally a further addition of low percentage of the carrier ordiluent; and (d) optionally repeating steps (c) and possibly (b) one ormore times.
 39. A process according to claim 20 , characterized byforming a drug mixture of dry active ingredient and fusible releasecontrol materials followed by mechanically working the mixture in a highspeed mixer with an energy input sufficient to melt or soften thefusible material whereby it forms particles with the active ingredient.40. A process according to claim 20 , comprising compressing particlesobtained by the process of claim 38 .
 41. A process according to claim20 , comprising compressing particles obtained by the process of claim39 .